Successful therapy of many different cancers is being severely curtailed by resistance to chemotherapeutic agents. Most studies of resistance have examined highly resistant cell lines which often show a multidrug resistance (MDR) phenotype. Low level resistant mutants also appear in the clinical setting and they may, as in vitro studies suggest, precede mutants expressing high level resistance. These studies propose to study a series of increasingly adriamycin resistant murine leukemia cell lines derived in this laboratory. Mutants appear with different levels of resistance to adriamycin, with/without concomitant resistance to vincristine and etoposide. The role and mechanistic basis of altered drug accumulation as a contributor to resistance will be assessed. Characterization and identification of the protein involved in the multiresistant cell line PC4- 40 which effluxes daunorubicin without over-expressing P-glycoprotein will be performed and the gene cloned. This research aims to define the role of decreased transport in resistance of early to intermediate level resistant mutants. Understanding the basis for resistance in the early mutants, which appear at levels and exposures of drug close to the clinical situation, may suggest new approaches to controlling the emergence of resistance as well as its progression to higher levels and cross-resistance phenotypes.